Opioid is a collective term for synthesis or endogenous peptides having alkaloid and morphine-like activities such as narcotic analgesics and related synthetic analgesics thereof. For the opioid receptors that are involved in the expression of the action of opioids, four kinds of subtypes of μ, κ, δ and ORL-1 are currently known. Among these, μ-opioid receptors are receptors that are the most relevant to the action of morphine, and besides morphine, fentanyl, and methionine enkephalin and β-endorphin, which are endogenous opioids, also act.
By administering morphine or fentanyl, which is a μ-opioid receptor agonist, itchiness occurs. Also in animal experiments, morphine induces scratching motions in spinal intrathecal administration in monkeys, administration from medullary dorsal horn in rats, and intracisternal administration in mice. Furthermore, since the itchiness in refractory pruritus diseases is ameliorated by μ-opioid receptor antagonist drugs, it is considered that the activation of μ opioid receptors by methionine enkephalin and β-endorphin, which are endogenous opioids, is involved in the occurrence of itchiness.
Since it has been confirmed in various clinical tests that μ-opioid receptor antagonist drugs such as naltrexone suppress itchiness in patients on dialysis and patients with cholestatic liver cirrhosis, the development of μ-opioid receptor antagonist drugs as anti-pruritus drugs is expected, but there has been no approved drug until now. In addition, side effects such as nausea, vomit, hyperalgesia such as stomach ache, and diarrhea are recognized in naltrexone, and thus naltrexone is not necessarily satisfiable as an anti-pruritus drug (Non Patent Literature 1). Therefore, creation of a μ-opioid receptor-selective medicament that causes less side effects and thus is highly safe is desired.
Until now, many 3-azabicyclo[3.1.0]hexane derivatives having a μ-opioid receptor-antagonistic activity have been reported (Patent Literatures 1 to 15, and Non Patent Literatures 2 to 4), but any of the compounds disclosed in these documents are different from the compounds of the present invention in structure.